Resolved
Authors: Peter Stenvinkel, Bengt Lindholm
Journal: Journal of the American Society of Nephrology (2008)

In contrast to the general population, an elevated body mass index (BMI) confers a survival advantage to patients with chronic kidney disease, as first described by Fleischmann et al. in 1999.1 This finding was subsequently confirmed in 54,535 hemodialysis patients showing that even BMI >35 kg/m2 was associated with a survival advantage.2 Moreover, a low percentage of body fat, or fat loss over time, was independently associated with higher mortality in 535 hemodialysis patients.3 However, in a group of 722 European hemodialysis patients, de Mutsert et al.4 found no survival advantage of BMI >30 kg/m2. There may be several reasons for these discrepant results. Obviously, the distribution and prevalence of obesity may be different in the United States compared with Europe. The cause of obesity is multifactorial and includes genetic factors, intrauterine nutrition (epigenetics), and environmental factors such as high-energy intake, more frequent consumption of beverages containing high-fructose corn syrup, low levels of physical activity, drugs, stress, viral infections, and sleep deficits. As the “obesity paradox” is stronger in black dialysis patients, and Asians on hemodialysis in the United States do not have better survival at higher BMI, results obtained in different races or ethnicities may not be readily comparable.5 Moreover, long-term mortality in the general population has usually been compared with short-term mortality in dialysis patients.4 This may not be a correct comparison because there are time discrepancies between competing risk factors. Indeed, short term-mortality, as a result of negative nitrogen balance and inflammatory disorders among other causes, is strongly associated with lower BMI in dialysis patients. Of note, there was an equal duration of follow-up between dialysis patients and the general population in the European study.4 Because the relationship between increased BMI and mortality seems to be less pronounced in the elderly general population, age-related mortality patterns may be another factor contributing to the observed association between elevated BMI and a survival benefit in dialysis patients. Another major problem when interpreting epidemiological studies is the use of BMI as a surrogate marker for fat mass because BMI does not differentiate between muscle and fat. The fact that BMI is not a reliable marker of fat mass is an important confounder. This is particularly true in dialysis patients where gross imbalances in fluid homeostasis are often observed. Because an increase in BMI may also be caused by more lean body mass, the association between increased BMI and better outcome does not necessarily imply that fat mass is protective. Indeed, Beddhu et al.6 showed in 70,028 hemodialysis patients (by evaluating 24-h urinary creatinine excretion as a measure of muscle mass) that the protective effect of increased BMI was limited to those with normal or high muscle mass. Although this study has been criticized on methodological grounds, 24-h urinary creatinine excretion is not only related to muscle mass but also renal function and protein intake, so it provides some insight into the association between BMI and outcome. In accordance, a Brazilian study of 344 hemodialysis patients showed that worse survival was found in patients with BMI >25 kg/m2 and a low muscle mass estimated by mid-arm muscle circumference.7 A recent study also demonstrated that a higher lean body mass was associated with lower risk of cardiovascular death.8 Moreover, protein-energy wasting, which also appears to be common (16%) in overweight (BMI > 25 kg/m2) stage 5 chronic kidney disease patients, is a predictor of mortality in these patients as well.9 Fat tissue is not simply a passive storage depot but the largest endocrine organ in the body, and it secretes a number of pleiotropic adipocytokines such as leptin, adiponectin, resistin, IL-6, and TNF-α.10 Because increased fat mass is associated with lower adiponectin levels, the recent observation by Menon et al.11 that high rather than low adiponectin levels were associated with increased mortality indirectly suggests that increased fat mass is not associated with a survival advantage in chronic kidney disease. Macrophages resident in adipose tissue are an important source of proinflammatory cytokines and promote oxidative stress and endothelial dysfunction.10 Because hepatic macrophages (Kupffer cells) make up the largest pool of fixed tissue macrophages and constitute approximately 70% of the total macrophage population in the body, the role of fat accumulation in the liver needs further attention in the context of uremia. Because increased fat mass is associated with metabolic derangements such as inflammation, insulin resistance, hyperadipokinemia and dyslipidemia, lower quality of life, and sleep apnea, a protective effect of increased fat mass on survival seems counterintuitive. An interesting alternative hypothesis addressing the question of why increased body size may be associated with better outcome was recently presented by Kotanko et al.12 Because generation of uremic toxins occurs predominantly in visceral organs, the generation of toxins per unit of BMI is lower in patients with high BMI who are often subjected to relatively more dialysis, if Kt/V is used to prescribe dose of dialysis. Indeed, because good appetite is associated with better outcome in hemodialysis patients,13 and obese patients consume more calories, this may indirectly explain the association between high BMI and better outcome. It should be appreciated that, besides detrimental metabolic effects, increased fat mass may also have, at least in theory, beneficial effects in the uremic milieu. Besides indicating well-preserved energy stores, the presence of obesity may be associated with improved hemodynamic tolerance, better stem cell mobilization, less stress response as a result of neurohormonal alterations, and more efficient disposal of lipophilic uremic toxins such as p-cresol and pentosidine. In a study of 808 hemodialysis patients, Kakiya et al.8 demonstrated that higher fat mass was associated with lower risk of noncardiovascular death. However, in this study no differentiation between different areas of fat tissue deposition was made. Because there are significant differences in metabolic activity, gene expression, hormonal sensitivity, and physiology between subcutaneous and visceral fat compartments, the relative importance of various fat stores should be relevant to this argument. Indeed, visceral fat mass is the most metabolically active fat store and a key factor in the development of insulin resistance, type-2 diabetes, and atherosclerosis. Although hemodialysis patients exhibit visceral fat accumulation associated with a disturbed lipid profile, insulin resistance, and carotid atherosclerosis irrespective of BMI,14 the differential effects of visceral versus subcutaneous fat stores on outcome has attracted surprisingly little interest. As preliminary data from Stockholm shows that increased visceral fat mass predicts poor outcome in male but not female dialysis patients, the impact of both gender and the distribution of fat tissue needs further investigation. On the basis of face-to-face interviews and questionnaires of 926 native Swedes with chronic kidney disease, Ejerblad et al.15 demonstrated that a high BMI was an important risk factor for chronic kidney disease, supporting the concept that obesity should be viewed as major preventable risk factor for renal progression. This is important new information because the majority of chronic kidney disease patients in the United States do not need dialysis.16 Thus, obese hemodialysis patients may constitute a selected group of survivors with a different genetic framework than their obese counterparts with chronic kidney disease who did not make it to end-stage. Little is known about genes associated with obesity and their relationship with other genetic traits affecting vascular health. However, emerging data suggest that fetuin-A, a circulating inhibitor of vascular calcification and ossification, is related to both insulin resistance and fat tissue accumulation.17 Thus, on the basis of a Swedish study showing that a common variant in the fetuin-A gene, which is associated with lower circulating fetuin-A levels, was more common among lean than obese and overweight men,18 it could be speculated that genetic traits associated with insulin resistance and fat tissue accumulation, rather than obesity per se, are associated with survival advantage in chronic kidney disease. Clearly, further studies are needed to see whether genetic traits associated with fat tissue accumulation are associated with survival advantage in chronic kidney disease. Whereas observational studies show that low BMI is associated with poor outcome in dialysis patients worldwide, epidemiological data relating high BMI to better outcome seems to differ between the United States and Europe. Clearly, cause and consequence can never be detected in cross-sectional studies. In our opinion, statistical fallacies, such as differences in observation time and age between the general population and dialysis patients, as well as differences in ethnicity and nutritional intake, may contribute to the observed discrepancies. It is also possible that obese patients starting dialysis treatment in the United State may constitute a selected group of survivors that endured the hardship of a longstanding unhealthy uremic milieu. Indeed, because decreased survival was found in 1759 North American patients with chronic kidney disease (GFR 39 ± 21 ml/min) with high BMI, obesity does not seem to be protective in mild to moderate chronic kidney disease.19 DISCLOSURES None. Baxter Healthcare employs Bengt Lindholm. We thank Reneé de Mutsert for valuable comments.